Originally discovered in the course of screening for microbial alkaloids, staurosporine and structurally related compounds have been the object of considerable investigation for various biomedical purposes for the past twenty years (for a review, see Omura, et al.). It has been recently reported that staurosporine and its derivatives, for example, inhibit smooth muscle contraction, platelet aggregation, neurotrophic activity, and, most importantly, protein kinases in vitro and in vivo (ibid.).
Disruption of cellular signal transduction via kinase malfunction has been related to the onset of several disease states, including rhematoid arthritis, systemic lupus erythematosis, diabetes metillus and Alzheimer's disease. For example, the clinical severity of Alzheimer's disease correlates well with the formation of amyloid plaques and neurofibrillary tangles; both manifest paired helical filaments (PHF) that possess an overphosphorylated microtubule associated protein (M.A.P., also known as .tau.-protein). It has been suggested that overphosphorylation may lead to conformational changes that inhibit .tau. binding to microtubules. Recently, a bovine .tau.-kinase denominated PK40 (molecular weight 40,000) has been isolated and shown to induce a gel mobility shift of PHF-.tau.. PK40 is not closely associated with the cytoskeleton and appears to be a member of the extracellular regulated kinases. Specific inhibition of enzymes like PK40 by small, orally bioavailable compounds, promise to be a highly successful means of treating Alzheimer's disease.
Unfortunately, the structural homology shared by the many kinase isozymes has impeded the development of selective and therapeutically useful inhibitors. It would be desirable to have others.